Epilepsy in the developing brain

Transcription

1 Epilepsy in the developing brain Dr Katherine Howell* Neurologist, Royal Children s Hospital Melbourne Clinician-Scientist Fellow, Murdoch Children s Research Institute Honorary Senior Fellow, University of Melbourne * With thanks to Simon Harvey

2 Overview Neurodevelopmental disorders in children with epilepsy Which children are at highest risk of developmental impairments and ultimately intellectual disability/cognitive impairment? Determinants of cognitive development Underlying cause Epileptic activity Anti-epileptic therapies 2

3 Neurodevelopmental disorders in children with epilepsy High rates of learning, intellectual, behavioural and emotional problems Community-based studies of all epilepsies in children report: Behavioural problems in 25% Intellectual problems in 20-26% Psychiatric symptoms in 10-30% Autism spectrum disorders in 5% Rutter et al, 1970; Schoenfeld et al, 1999; Lendt et al, 2000; Binnie, 2001; Davies et al, 2003; Berg AT et al, 2008, 2011,

4 Primary determinants of development 613 children with new-onset epilepsy followed for median 10 years (Connecticut) Primary determinants of development: early age at seizure onset, underlying cause, frequent seizures and EEG abnormalities, drug-resistance Berg AT et al. Epilepsia

5 Early age of epilepsy onset More severe conditions Brain more vulnerable to insults Critical postnatal developmental processes Development of skills step-wise, builds on previously acquired skills 5

6 Epileptic activity Underlying cause Vulnerable substrate Antiepileptic drugs

7 Underlying cause: poorer outcomes in symptomatic epilepsies 7

8 Improving development by treating the underlying cause? preventable conditions eg. perinatal hypoglycaemic/hie injury, post-traumatic epilepsy (public health) reversible conditions eg. B6, folinic acid, biotin, creatine, serine deficiency syndromes (supplement), hyperinsulinism (glucose, diazoxide) treatable conditions eg. glucose transporter disorder (ketogenic diet), tumours/dysplasias (surgery) manageable conditions eg. idiopathic/genetic epilepsies, non-operable focal epilepsies (AEDs, KD, VNS) irreversible conditions eg. chromosomopathies, genetic EEs, diffuse brain abn. (AEDs, KD, VNS) progressive conditions eg. progressive myoclonic epilepsies, neoplasms, Rasmussen (AEDs) 8

9 Frequent seizures and EEG abnormality: epileptic encephalopathy Epileptic encephalopathy embodies the notion that the epileptic activity itself may contribute to severe cognitive and behavioural impairments above and beyond what might be expected from the underlying pathology alone (eg cortical malformation), and that these can worsen over time. Berg et al, Revised ILAE Classification Report,

10 Epileptic encephalopathy Epileptic activity Underlying cause Cognitive impairment 10

11 normal child abilities (motor, language, cognitive etc) epileptic encephalopathy child with static cerebral abnormality (without frequent seizures) infant preschool school-age adult age

12 Which children with epilepsy have an epileptic encephalopathy? Infants/younger children >> older children and adults Particular epileptic syndromes E.g. infantile spasms (West syndrome), Lennox Gastaut syndrome, Landau Kleffner syndrome Any epilepsy with very frequent seizures (often multiple daily) prominent epileptiform abnormality on EEG 12

13 Infantile spasms Most common type of severe epilepsy in infants 1:3000 infants Many causes Features of the seizures Look like a startle Occur in clusters Most commonly on waking Multiple times per day Additional features = West syndrome Developmental plateau or regression Developmental outcome subnormal in ~80% EEG hypsarrhythmia 13

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15 Effect of treatment lag in infantile spasms (IS) provides evidence of epileptic encephalopathy Better developmental outcomes with short lead-time to treatment IS of any cause (except tuberous sclerosis) 16 point IQ drop with 2 month delay to treatment IS due to Trisomy 21 Treatment lag <2 months: median IQ 37 Treatment lag >2 months: median IQ 14, higher rates of ASD Cryptogenic IS (unknown cause AND normal development prior to IS) Treatment lag <1 month: 100% normal cognition Treatment lag 1-6 months: 40% normal cognition Dose-dependent effect of IS shown in prospective study of tuberous sclerosis Drop in IQ with spasm onset Progressive decline in IQ with increased duration of exposure to IS Eisermann, 2003; Kivity, 2004; O Callaghan, 2011; Humphrey,

16 Prevention is better than prompt treatment: pre-treatment in tuberous sclerosis Commencement of preventative vigabatrin improves developmental outcomes at age 2 years Fewer patients with intellectual disability (14% vs 48%) Higher mean IQ (92 vs 69) Screening EEGs +/- vigabatrin pre-treatment is now standard of care in tuberous sclerosis Jozwiak,

17 Epilepsy surgery provides evidence that developmental impacts of epileptic encephalopathy are potentially reversible Progessive developmental impairment in early-life epilepsies with frequent seizures Epilepsy surgery halts developmental decline Median 30 point DQ increase with epilepsy surgery before age 1 year Berg, 2004; Loddenkemper,

18 Epileptic encephalopathy: critical points Developmental impacts are: Due to the epileptic activity Progressive Potentially reversible Developmental impact can be reduced by early diagnosis and early, effective treatment Prevention (where possible) is better than early treatment 18

19 How does epileptic activity affect development? Impede or interrupt normal processes Overt brain injury due to excitotoxic neurotransmitter release, local metabolic compromise, inflammation Effect on postnatal brain development Cellular excitability Neuronal connections Activity-dependent synaptogenesis Dendritic arborisation Neuronal migration/organisation Neurogenesis Cellular survival 19

20 Effects on the neuron synaptic reorganisation neurogenesis neuronal cell loss glial activation protein expression kinase activation early gene activation Ca ++ influx min 1 hour 1 day 1 week time (secs) seizure Cole,

21 Effects on neuronal connections: example of synaptic proliferation and elimination Maximum synaptic number/density is between 6-24 months, with subsequent pruning of redundant synapses Synaptic elimination and reinforcement is activity-dependent and strongly influenced by glutamate/ GABA balance at synapses Huttenlocher,

22 Developmental impacts of antiepileptic drugs (AEDs) Direct evidence: phenobarbitone use in infancy for FS prophylaxis was associated with permanent lowering of IQ by 5-10 points low IQ, ADHD and autism rates increased in children born to mothers with epilepsy taking AEDs esp. valproate fetal AED syndrome Presumed effects: effects of AEDs on cognition, fluency, behaviour and mood reported in adults and children presumably relevant in a developmental context Nelson & Ellenberg, 1978; Farwell, 1990; Vinten, 2005; Gaily, 2004; Rasalam, 2005; Meador, 2009; Meador & Loring, 2013; Bromley,

23 How do AEDs impact development? AED actions different in the immature brain to adults AED due to developmental differences in receptors E.g. GABAergic drugs depolarising AED effects can impair cellular and network processes in postnatal brain development Cellular excitability Neuronal connections Activity-dependent synaptogenesis Dendritic arborisation Neuronal migration/organisation Neurogenesis Cellular survival Kirmse et al, 2011; Bittigau, Proc Natl Acad Sci USA 2002; Ikonomidou, Science

24 Reducing impact of AEDs on development Consider whether treatment needed at all (may not be in benign seizure disorders) Understand which AEDs more likely to impact development Phenobarbitone, benzodiazepines, valproate and vigabatrin Reduce and rationalise polypharmacy where possible Tailor AED choice to type of epilepsy Optimise drug combinations for efficacy and to reduce pharmacodynamic effects Using non-aed epilepsy treatments to reduce/obviate AED use e.g. epilepsy surgery, vagus nerve stimulator 24

25 Epileptic activity Underlying cause Vulnerable substrate Antiepileptic drugs

26 Recommendations for improving developmental outcomes Identify children with epilepsy at risk of impaired development Identify underlying cause (especially treatable causes) Accurately characterise the epilepsy and likely presence of epileptic encephalopathy Guide treatment choice and urgency Rational choice of AEDs (sometimes no AEDs) Get expert advice/assistance in young children with epilepsies that have potential developmental impact Monitor seizure control, EEG, development Prevention of epilepsy in high-risk children (e.g. with tuberous sclerosis) 26

27 Thank you! 27